Bicyclic derivatives as modulators of voltage gated ion channels

ABSTRACT

Bicyclic derivatives useful as ion channel antagonists are disclosed herein. The compositions thereof are useful for treating or relieving pain-related conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit under 35 U.S.C. §119 of U.S.Provisional Application No. 60/715,980, filed Sep. 9, 2005, the entirecontents of the above application being incorporated herein byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table A, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259(1): 213-6).

TABLE A (Abbreviations: CNS = central nervous system, PNS = peripheralnervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Naisoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS soma of 10 nM Pain,Epilepsy, neurons neurodegeneration NaV1.2 CNS, high in axons 10 nMNeurodegeneration Epilepsy NaV1.3 CNS, embryonic, 15 nM Pain injurednerves NaV1.4 Skeletal muscle 25 nM Myotonia NaV1.5 Heart 2 μMArrythmia, long QT NaV1.6 CNS widespread, 6 nM Pain, movement disordersmost abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminalsdisorders neuroendocrine NaV1.8 PNS, small neurons >50 μM Pain in DRG &TG NaV1.9 PNS, small neurons 1 μM Pain in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.), bupivacaine, phenyloin(See, Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain:rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8),lamotrigine (See, Rozen, T. D. (2001) “Antiepileptic drugs in themanagement of cluster headache and trigeminal neuralgia” Headache 41Suppl 1: S25-32 and Jensen, T. S. (2002) “Anticonvulsants in neuropathicpain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8.),and carbamazepine (See, Backonja, M. M. (2002) “Use of anticonvulsantsfor treatment of neuropathic pain” Neurology 59(5 Suppl 2): S14-7), havebeen shown to be useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62.). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV 1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states, there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83(3):591-600.) The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21(16): 5952-61.). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9.). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T.,L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channelsin painful human neuroma-evidence from immunocytochemistry” ActaNeurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 arealso expressed in dorsal root ganglion neurons and contribute to thesmall TTX sensitive component seen in these cells. NaV1.7 in particularmay therefore be a potential pain target in addition to its role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v)1.2 in a patient with febrile and afebrile seizurescauses channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) havebeen linked to epilepsy conditions including febrile seizures. There areover 9 genetic mutations in NaV1.1 associated with febrile seizures(See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations ofvoltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); for neuroprotection (See, Taylor, C. P. andL. S, Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See,Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain.” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994;42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104(2):191-8); neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67(1):87-97); chronic visceral pain, includingabdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000;119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol.2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark,Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al.,J Neurophysiol. 1999; 81(2):479-93); tension headache, including clusterheadaches (see, Costa, A., et al., Cephalalgia. 2000; 20(2):85-91);chronic neuropathic pain, including post-herpetic neuralgia (see, Attal,N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain50:355); diabetic neuropathy (see, Beidoun A et al., Clin J Pain. 2004;20(3):174-8; Courteix, C., et al., Pain. 1993; 53(1):81-8);HIV-associated neuropathy (see, Portegies & Rosenberg, Ned TijdschrGeneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004;107(1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35);trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med OralPathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp BrainRes. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda,M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensoryneuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003;12(15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27);radiculopathy (see, Devers & Galer, (see, Clin J Pain. 2000;16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapyinduced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996;73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomypain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain(Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cordinjury pain (see, Hains, B. C., et al., Exp Neurol. 2000;164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., etal., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome(see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; XantosD et al., J Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W.E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain.1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can JAnaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see,Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J.,et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; jointpain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22);mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000;85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay,M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain,including abdominal pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; etc (see, Giambernardino, M. A., etal., Pain. 1995; 61(3):459-69); chest pain, including cardiac Pain (see,Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvic pain,renal colic pain, acute obstetric pain, including labor pain (see,Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesarean sectionpain; acute inflammatory, burn and trauma pain; acute intermittent pain,including endometriosis (see, Cason, A. M., et al., Horm Behav. 2003;44(2):123-31); acute herpes zoster pain; sickle cell anemia; acutepancreatitis (see, Toma, H; Gastroenterology. 2000; 119(5):1373-81);breakthrough pain; orofacial pain, including sinusitis pain, dental pain(see, Nusstein, J., et al., J Endod. 1998; 24(7):487-91; Chidiac, J. J.,et al., Eur J Pain. 2002; 6(1):55-67); multiple sclerosis (MS) pain(see, Sakurai & Kanazawa, J Neurol Sci. 1999; 162(2):162-8); pain indepression (see, Greene B, Curr Med Res Opin. 2003; 19(4):272-7);leprosy pain; behcet's disease pain; adiposis dolorosa (see, Devillers &Oranje, Clin Exp Dermatol. 1999; 24(3):240-1); phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain (see, Legroux-Crespel, E., et al., Ann DermatolVenereol. 2003; 130(4):429-33); Fabry's disease pain (see, Germain, D.P., J Soc Biol. 2002; 196(2):183-90); Bladder and urogenital disease,including urinary incontinence (see, Berggren, T., et al., J Urol. 1993;150(5 Pt 1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al.,Urology. 2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura,N., et al., J. Neurosci. 2001; 21(21):8690-6); interstitial cyctitis(IC) (see, Giannakopoulos& Campilomatos, Arch Ital Urol Nefrol Androl.1992; 64(4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); andprostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith,I. M., et al., J Urol. 2001; 166(1):323-8).

Voltage-gated calcium channels are membrane-spanning, multi-subunitproteins that open in response to membrane depolarization, allowing Caentry from the extracellular milieu. Calcium channels were initiallyclassified based on the time and voltage-dependence of channel openingand on the sensitivity to pharmacological block. The categories werelow-voltage activated (primarily T-type) and high-voltage activated (L,N, P, Q or R-type). This classification scheme was replaced by anomenclature based upon the molecular subunit composition, as summarizedin Table B (Hockerman G H, Peterson B Z, Johnson B D, Catterall W A.1997. Annu Rev Pharmacol Toxicol 37: 361-96; Striessnig J. 1999. CellPhysiol Biochem 9: 242-69). There are four primary subunit types thatmake up calcium channels—α₁, α₂δ, β and γ (See, e.g., De Waard et al.Structural and functional diversity of voltage-activated calciumchannels. In Ion Channels, (ed. T. Narahashi) 41-87, (Plenum Press, NewYork, 1996)). The α₁ subunit is the primary determinant of thepharmacological properties and contains the channel pore and voltagesensor (Hockerman et al., 1997; Striessnig, 1999). Ten isoforms of theα₁ subunit are known, as indicated in Table I below. The α₂δ subunitconsists of two disulfide linked subunits, α₂, which is primarilyextracellular, and a transmembrane δ subunit. Four isoforms of α₂δ areknown, α₂δ-1, α₂δ-2, α₂δ-3 and α₂δ-4. The β subunit is anon-glycosylated cytoplasmic protein that binds to the α₁ subunit. Fourisoforms are known, termed β₁ to β₄. The γ subunit is a transmembraneprotein that has been biochemically isolated as a component of Ca_(v)1and Ca_(v)2 channels. At least 8 isoforms are known (γ₁ to γ₈) [Kang MG, Campbell K P. 2003. J Biol Chem 278: 21315-8]. The nomenclature forvoltage-gated calcium channels is based upon the content of the α₁subunit, as indicated in Table I. Each type of α₁ subunit can associatewith a variety of β, α₂δ or γ subunits, so that each Ca_(v) typecorresponds to many different combinations of subunits.

TABLE B Cav Nomenclature α₁ subunit Pharmacological name Ca_(v)1.1α_(1S) L-type Ca_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4α_(1F) Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3α_(1E) R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3α_(1I) T-type

Ca_(v)2 currents are found almost exclusively in the central andperipheral nervous system and in neuroendocrine cells and constitute thepredominant forms of presynaptic voltage-gated calcium current.Presynaptic action potentials cause channel opening, andneurotransmitter release is steeply dependent upon the subsequentcalcium entry. Thus, Ca_(v)2 channels play a central role in mediatingneurotransmitter release.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for thepeptide toxins ω-conotoxin-MVIIC and ω-conotoxin-GVIA, respectively, andthese peptides have been used to determine the distribution and functionof each channel type. Ca_(V)2.2 is highly expressed at the presynapticnerve terminals of neurons from the dorsal root ganglion and neurons oflamina I and II of the dorsal horn (Westenbroek R E, Hoskins L,Catterall W A. 1998. J Neurosci 18: 6319-30; Cizkova D, Marsala J,Lukacova N, Marsala M, Jergova S, et al. 2002. Exp Brain Res 147:456-63). Ca_(V)2.2 channels are also found in presynaptic terminalsbetween second and third order interneurons in the spinal cord. Bothsites of neurotransmission are very important in relaying paininformation to the brain.

Pain can be roughly divided into three different types: acute,inflammatory, and neuropathic. Acute pain serves an important protectivefunction in keeping the organism safe from stimuli that may producetissue damage. Severe thermal, mechanical, or chemical inputs have thepotential to cause severe damage to the organism if unheeded. Acute painserves to quickly remove the individual from the damaging environment.Acute pain by its very nature generally is short lasting and intense.Inflammatory pain on the other had may last for much longer periods oftime and it's intensity is more graded. Inflammation may occur for manyreasons including tissue damage, autoimmune response, and pathogeninvasion. Inflammatory pain is mediated by an “inflammatory soup” thatconsists of substance P, histamines, acid, prostaglandin, bradykinin,CGRP, cytokines, ATP, and neurotransmitter release. The third class ofpain is neuropathic and involves nerve damage that results inreorganization of neuronal proteins and circuits yielding a pathologic“sensitized” state that can produce chronic pain lasting for years. Thistype of pain provides no adaptive benefit and is particularly difficultto treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmetmedical need. Millions of individuals suffer from severe pain that isnot well controlled by current therapeutics. The current drugs used totreat pain include NSAIDS, COX2 inhibitors, opioids, tricyclicantidepressants, and anticonvulsants. Neuropathic pain has beenparticularly difficult to treat as it does not respond well to opiodsuntil high doses are reached. Gabapentin is currently the favoredtherapeutic for the treatment of neuropathic pain although it works inonly 60% of patients where it shows modest efficacy. The drug is howeververy safe and side effects are generally tolerable although sedation isan issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic painis provided by studies with ziconotide (also known asω-conotoxin-MVIIA), a selective peptide blocker of this channel(Bowersox S S, Gadbois T, Singh T, Pettus M, Wang Y X, Luther R R. 1996.J Pharmacol Exp Ther 279: 1243-9; Jain K K. 2000. Exp. Opin. Invest.Drugs 9: 2403-10; Vanegas H, Schaible H. 2000. Pain 85: 9-18) In man,intrathecal infusion of Ziconotide is effective for the treatment ofintractable pain, cancer pain, opioid resistant pain, and neuropathicpain. The toxin has an 85% success rate for the treatment of pain inhumans with a greater potency than morphine. An orally availableantagonist of Ca_(V)2.2 should have similar efficacy without the needfor intrathecal infusion. Ca_(V)2.1 and Ca_(V)2.3 are also in neurons ofnociceptive pathways and antagonists of these channels could be used totreat pain.

Antagonists of Ca_(V)2.1, Ca_(V)2.2, or Ca_(V)2.3 should also be usefulfor treating other pathologies of the central nervous system thatapparently involve excessive calcium entry. Cerebral ischaemia andstroke are associated with excessive calcium entry due to depolarizationof neurons. The Ca_(V)2.2 antagonist ziconotide is effective in reducinginfarct size in a focal ischemia model using laboratory animals,suggesting that Ca_(V)2.2 antagonists could be used for the treatment ofstroke. Likewise, reducing excessive calcium influx into neurons may beuseful for the treatment of epilepsy, traumatic brain injury,Alzheimer's disease, multi-infarct dementia and other classes ofdementia, amyotrophic lateral sclerosis, amnesia, or neuronal damagecaused by poison or other toxic substances.

Ca_(V)2.2 also mediates release of neurotransmitters from neurons of thesympathetic nervous system and antagonists could be used to treatcardiovascular diseases such as hypertension, cardiac arrhythmia, anginapectoris, myocardial infarction, and congestive heart failure.

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Accordingly,there remains a need to develop additional Na channel and Ca channelantagonists, preferably those with higher potency and fewer sideeffects. Unfortunately, as described above, the efficacy of currentlyused sodium channel blockers and calcium channel blockers for thedisease states described above has been to a large extent limited by anumber of side effects. These side effects include various CNSdisturbances such as blurred vision, dizziness, nausea, and sedation aswell more potentially life threatening cardiac arrhythmias and cardiacfailure. Accordingly, there remains a need to develop additional Nachannel and Ca channel antagonists, preferably those with higher potencyand fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels and calcium channels. Thesecompounds have the general formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head, or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds of formula Ithat are useful as inhibitors of voltage-gated sodium channels andcalcium channels.

or a pharmaceutically acceptable salt thereof;

wherein:

one of X and W is N or CH and the other of X and W is CH;

ring Z is a 5-7 membered unsaturated or aromatic ring having at leastone ring heteroatom selected from O, S, N, or NH, wherein Z isoptionally substituted with up to z occurrence of R^(Z);

z is 0 to 4;

each R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵;

the SO₂ group is attached to either carbon no. 1 or 2;

the ring containing W and X is optionally substituted with up to 4substituents selected from halo, CN, NO₂, CF₃, OCF₃, OR⁶, SR6, S(O)R²,SO₂R², NH₂, N(R²)₂, COOR², or C1-C6 straight or branched alkylidinechain, wherein up to two non-adjacent methylene units of said alkylidineare optionally and independently replaced by —CO—, —CS—, —COCO—,—CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—,—NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—,or —NR²SO₂NR²—;

Q is a bond or is a C1-C6 straight or branched alkylidine chain, whereinup to two non-adjacent methylene units of Q are optionally andindependently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—,—CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—,—NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or aspirocycloalkylene moeity;

R^(Q) is a C₁₋₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from O, S, N, orNH;

wherein R^(Q) is optionally substituted with up to 4 substituentsselected from R¹, R², R³, R⁴, or R⁵;

R^(M) and R^(N) are independently R²;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶, or (CH₂)_(n)—Y;

n is 0, 1, or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶, or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, optionally substituted with up to 3 substituents,independently selected from R¹, R², R⁴, or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, optionally substituted with up to 3 R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently chosen from H, C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic,S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic,N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and

R⁸ is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl;

provided that:

-   -   (i) when ring Z is optionally substituted pyridyl, W is C, and X        is C, then Q—R^(Q), taken together is not optionally substituted        phenyl;    -   (ii) when W is CH, and X is CH, then Q-R^(Q) taken together is        not methyl.

In another embodiment, the present invention provides compounds offormula II:

wherein:

ring Z is a 5-7 membered unsaturated or aromatic ring having at leastone ring heteroatom selected from O, S, N, or NH, wherein Z isoptionally substituted with up to z occurrence of R^(Z);

z is 0 to 4;

each R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵;

the SO₂ group is attached to either carbon no. 1 or 2;

the NR²C(O) group is attached to either carbon no. 5 or 6;

wherein the ring containing carbons no. 5 and 6 is optionallysubstituted with up to 4 substituents selected from halo, CN, NO₂, CF₃,OCF₃, OR⁶, SR⁶, S(O)R², SO₂R², NH₂, N(R²)₂, COOR², or C1-C6 straight orbranched alkylidine chain, wherein up to two non-adjacent methyleneunits of said alkylidine are optionally and independently replaced by—CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—,—NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO, —SO₂—,—NR²—, —SO₂NR²—, NR²SO₂—, or —NR²SO₂NR²—;

Q is a bond or is a C1-C6 straight or branched alkylidine chain, whereinup to two non-adjacent methylene units of Q are optionally andindependently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—,—CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—,—NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or aspirocycloalkylene moeity;

R^(Q) is a C₁₋₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from O, S, N, orNH;

wherein R^(Q) is optionally substituted with up to 4 substituentsselected from R¹, R², R³, R⁴, or R⁵;

R^(M) and R^(N) are independently R²;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶, or (CH₂)_(n)—Y;

n is 0, 1, or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶, or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, optionally substituted with up to 3 substituents,independently selected from R¹, R², R⁴, or R⁵;

R⁴ is OR^(S), OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR^(S), S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂,SO₂NR⁵R⁶, SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂,C(O)N(R⁵)₂, C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵,C(O)N(OR⁵)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂,N(R⁵)₂, N(R⁵R⁶), NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶,NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶,NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶,NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂,NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶,P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶),P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, orP(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, optionally substituted with up to 3 R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR² substituent;

R² is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R² is optionally substituted with up to 2substituents independently chosen from H, C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic,S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic,N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and

R⁸ is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl;

provided that:

-   -   (i) Q-R^(Q), taken together is not methyl or isopropyl;    -   (ii) ring Z is not optionally substituted isoxazolyl,    -   (iii) when ring Z is optionally substituted piperazinyl, then R²        is not methyl; and    -   (iv) when ring Z is optionally substituted piperazinyl, Q is O,        then R^(Q) is not benzyl.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable (i.e.,having the requisite valency available for a given substituent) positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” means a monocyclichydrocarbon, bicyclic, or tricyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. In some embodiments, “cycloaliphatic” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic, that has a single point of attachment to the rest ofthe molecule wherein any individual ring in said bicyclic ring systemhas 3-7 members.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” as used herein meansnon-aromatic, monocyclic, bicyclic, or tricyclic ring systems in whichone or more ring atoms in one or more ring members is an independentlyselected heteroatom. Heterocyclic ring can be saturated or can containone or more unsaturated bonds. In some embodiments, the “heterocycle”,“heterocyclyl”, or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including any oxidized form of nitrogen, sulfur, phosphorus, orsilicon; the quaternized form of any basic nitrogen, or a substitutablenitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

The term “spirocycloalkylene” refers to a cycloaliphatic ring that hastwo points of attachment from the same carbon atom to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

In one embodiment, X is N and W is CH. Or, X is CH and W is N. Inanother embodiment, each X and W is independently CH.

In one embodiment, Z is an optionally substituted ring selected from:

In certain embodiments of the compounds of the present invention, Z isselected from:

wherein Z has up to two substituents selected from R¹, R², or R⁵.

In other embodiments, Z is selected from:

Or, Z is formula a-i-a.

In other embodiments, Z is selected from:

In certain embodiments of the present invention, Z is selected from:

Or, Z is selected from:

Or, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

In other embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

According to one embodiment of formula (I), R¹ is oxo. Or R¹ is═NN(R⁶)₂, ═NN(R⁷)₂, or ═NN(R⁶R⁷). According to another embodiment, R¹ isR⁶.

According to one embodiment, R¹ is (CH₂)_(n)—Y. Or, R¹ is Y.

Exemplary Y includes halo, CN, NO2, CF₃, OCF₃, OH, SH, S(C1-4aliphatic), S(O)(C1-4 aliphatic), SO₂(C1-4 aliphatic), NH₂, NH(C1-4aliphatic), N(C1-4 aliphatic)₂, NR(C1-4 aliphatic)R⁸, COOH, COO(C1-4aliphatic), or O(C1-4 aliphatic). Or, two R¹ on adjacent ring atoms,taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy. In anotherembodiment, Y is halo, OH, SH, CN, NO₂, CF₃, OCF₃, COOH, or C(O)O(C1-C4alkyl). In another embodiment, R¹ is selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, orC(O)C₁₋₄ alkyl.

In another embodiment, R¹ is (CH₂)_(n)—Y. In one embodiment, n is 0or 1. Or, n is 2. In one embodiment, Y is halo, CN, NO₂, CF₃, OCF3, OR⁶,SR⁶, S(O)R⁶, SO₂R⁶, N(R⁶)₂, NR⁶R⁸, or COOR⁶. In another embodiment, Y ishalo, OH, SH, CN, NO₂, CF₃, OCF₃, or C(O)O(C1-C4 alkyl).

In one embodiment, two R¹ on adjacent ring atoms, taken together, form1,2-methylenedioxy or 1,2-ethylenedioxy.

According to another preferred embodiment of formula (I), R² is astraight or branched (C1-C6) alkyl or (C2-C6)alkenyl or alkynyl,optionally substituted with up to two R¹ substitutions.

In one embodiment, R² is C1-C6 aliphatic. In another embodiment, R² is aC1-C6 straight or branched alkyl. In another embodiment, R² is C1-C4alkyl. In another embodiment, R² is optionally substituted with up to 2substituents independently selected from R¹ or R⁴. Or, R² is optionallysubstituted with up to 2 substituents independently selected from R¹ orR⁵.

In one embodiment, R³ is a C3-C8 cycloaliphatic optionally substitutedwith up to 3 substituents independently selected from R¹, R², R⁴, or R⁵.Exemplary cycloaliphatics include cyclopropyl, cyclopentyl, cyclohexyl,or cycloheptyl. In another embodiment, R³ is a C6-C10 aryl, optionallysubstituted with up to 3 substituents, independently selected from R¹,R², R⁴, or R⁵. Exemplary aryl rings include phenyl or naphthyl. Inanother embodiment, R³ is a C3-C8 heterocyclic, optionally substitutedwith up to 3 substituents, independently selected from R¹, R², R⁴, orR⁵. Exemplary heterocyclic rings include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In anotherembodiment, R³ is a C5-C10 heteroaryl ring, optionally substituted withup to 3 substituents, independently selected from R¹, R², R⁴, or R⁵.Exemplary heteroaryl rings include pyridyl, pyrazyl, triazinyl, furanyl,pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,imidazolyl, triazolyl, thiadiazolyl, pyrimidinyl. quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothiophenyl, indolizinyl, indolyl, isoindolyl,indolinyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl,cinnolinyl, phthalazine, quinazolinyl, quinaoxalinyl, naphthylirinyl, orpteridinyl.

In one embodiment, R⁴ is selected from OR⁵ or OR⁶. Or, R⁴ is selectedfrom OC(O)R⁶ or OC(O)R⁵. In another embodiment, R⁴ is selected fromC(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂, orC(O)N(R⁵R⁶). In yet another embodiment, R⁴ is selected from N(R⁶)₂,N(R⁵)₂, or N(R⁵R⁶). Or, R⁴ is selected from NR⁵C(O)R⁵, NR⁶C(O)R⁶,NR⁶C(O)R⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, or NR⁵C(O)N(R⁵)₂.

In one embodiment, R⁵ is a C3-C8 cycloaliphatic, optionally substitutedwith up to 3 R¹ substituents. Exemplary cycloaliphatics includecyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl. In anotherembodiment, R⁵ is a C6-C10 aryl, optionally substituted with up to 3 R¹substituents. Exemplary aryl rings include phenyl or naphthyl. Inanother embodiment, R⁵ is a C3-C8 heterocyclic, optionally substitutedwith up to 3 R¹ substituents. Exemplary heterocyclic rings includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl. In another embodiment, R⁵ is a C5-C10 heteroaryl ring,optionally substituted with up to 3 R¹ substituents. Exemplaryheteroaryl rings include pyridyl, pyrazyl, triazinyl, furanyl, pyrrolyl,thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl,triazolyl, thiadiazolyl, pyrimidinyl. quinolinyl, isoquinolinyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazine,quinazolinyl, quinaoxalinyl, naphthyridinyl, or pteridinyl.

In one embodiment, R⁶ is H. In another embodiment, R⁶ is C1-C6aliphatic, preferably, C1-C6 alkyl. Or, R⁶ is C1-C6 aliphatic optionallysubstituted with a R⁷ substituent.

In one embodiment, R⁷ is a C3-C8 cycloaliphatic, optionally substitutedwith up to 2 substituents independently chosen from H, C1-C6 aliphatic,or (CH₂)_(m)—Z′ wherein m is 0-2. Exemplary cycloaliphatics includecyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl. In anotherembodiment, R⁷ is a C6-C10 aryl, optionally substituted with up to 2substituents independently chosen from H, C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2. Exemplary aryl rings include phenyl ornaphthyl. Or, R⁷ is a C3-C8 heterocyclic, optionally substituted with upto 2 substituents independently chosen from H, C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2. Exemplary heterocyclic rings includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl. Or, R⁷ is a C5-C10 heteroaryl ring, optionallysubstituted with up to 2 substituents independently chosen from H, C1-C6aliphatic, or (CH₂)_(m)—Z′ wherein m is 0-2. Exemplary heteroaryl ringsinclude pyridyl, pyrazyl, triazinyl, furanyl, pyrrolyl, thiophenyl,oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl, triazolyl,thiadiazolyl, pyrimidinyl. quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazine,quinazolinyl, quinaoxalinyl, naphthyridinyl, or pteridinyl.

In one embodiment, Z′ is selected from halo, CN, NO₂, C(halo)₃,CH(halo)₂, CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH,S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic.

In one embodiment, Q is a bond.

In another embodiment, Q is O, S, or NR². In embodiment, Q is O. Or, Qis S. Or, Q is NR². Or, Q is NH or N(C1-C6) alkyl.

In another embodiment, Q is a C1-C6 straight or branched alkylidinechain, wherein up to one methylene unit of Q is replaced by O, S, NH, orN(C1-C4 alkyl).

In another embodiment, Q is a C1-C6 alkyl, wherein one methylene groupis replaced by a spirocycloalkylene group such as spirocyclopropylene.

In another embodiment, Q is —X₂—(X₁)_(p)—, wherein:

X₂ is C1-C6 aliphatic, optionally substituted with up to twosubstituents independently selected from R¹, R⁴, or R⁵; and

p is 0 or 1; and

X₁ is O, S, or NR².

In one embodiment, X₂ is C1-C6 alkyl or C2-C6 alkylidene. Or, X₂ isC1-C6 alkyl optionally substituted with R¹ or R⁴. In one embodiment, X₂is selected from —CH₂—, —CH₂—CH₂—, —(CH₂)₃—, —C(Me)₂-, —CH(Me)—,—C(Me)═CH—, —CH═CH—, —CH(Ph)—, —CH₂—CH(Me)—, —CH(Et)—, or —CH(i-Pr)—.

In certain embodiments, X₁ is NH. Or, X₁ is —N(C1-C4 alkyl)-.

In one embodiment, p is 0.

In another embodiment, p is 1 and X₁ is O.

In another embodiment, p is 1, and X₁ is S.

In another embodiment, p is 1, and X₁ is NR². Preferably, R² ishydrogen.

In one embodiment, R^(Q) is a C₁₋₆ aliphatic group, wherein R^(Q) isoptionally substituted with up to 4 substituents selected from R¹, R²,R³, R⁴, or R⁵.

In another embodiment, R^(Q) is a 3-8-membered saturated, partiallyunsaturated, or aromatic monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, wherein R^(Q) is optionallysubstituted with up to 4 substituents selected from R¹, R², R³, R⁴, orR⁵. In one embodiment, e is optionally substituted with up to 3substituents selected from halo, cyano, trifluoromethyl, OH, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, R^(Q) is optionally substituted phenyl, wherein R^(Q)is optionally substituted with up to 4 substituents selected from R¹,R², R³, R⁴, or R⁵. In one embodiment, R^(Q) is phenyl optionallysubstituted with up to 3 substituents selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, R^(Q) is optionally substituted naphthyl, whereinR^(Q) is optionally substituted with up to 4 substituents selected fromR¹, R², R³, R⁴, or R⁵. In one embodiment, R^(Q) is naphthyl optionallysubstituted with up to 5 substituents selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

Or, R^(Q) is an optionally substituted 3-8 membered cycloaliphatic ring,wherein R^(Q) is optionally substituted with up to 4 substituentsselected from R¹, R², R³, R⁴, or R⁵. In one embodiment, R^(Q) isselected from optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

Or, R^(Q) is an optionally substituted 5-6 membered monocyclic,unsaturated, partically saturated, or aromatic ring containing up to 3heteroatoms independently selected from O, S, N, or NH. Or, R^(Q) is a3-7 membered monocyclic, heterocyclic ring.

In one embodiment, R^(Q) is selected from an optionally substituted ringselected from:

In another embodiment, R^(Q) is selected from any of rings i-xiv or xvi,wherein said ring is fused to an optionally substituted phenyl ring.

In another embodiment, R^(Q) is selected from an optionally substitutedring selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is any one of the above rings xvii-xxiv,wherein said ring is fused to an optionally substituted phenyl ring.

In another embodiment, R^(Q) is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from O, S, N, or NH, wherein R^(Q) isoptionally substituted with up to 4 substituents selected from R¹, R²,R³, R⁴, or R⁵. In one embodiment, R^(Q) is optionally substitutednaphthyl. Or, R^(Q) is an optionally substituted 8-10 membered,bicyclic, heteroaromatic ring. Or, R^(Q) is an optionally substituted,8-10 membered, bicyclic, heterocyclic ring.

In one embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is selected from the following:

In one embodiment, wherein R^(Q) is selected from 2-fluoro-phen-1-yl,phenyl, 3-chloro-phen-1-yl, 4-chloro-phen-1-yl, 4-tert-butyl-phen-1-yl,2,5-difluoro-phen-1-yl, 3,4-dichloro-phen-1-yl,3-chloro-4-fluoro-phen-1-yl, or indol-1-yl.

In one embodiment, the present invention provides compounds of formulaI-A or formula I-B:

wherein ring Z, R², W, X, Q, and R^(Q) are as defined above.

In one embodiment of formula I-A or formula I-B, W is N and X is CH.

In another embodiment of formula I-A or formula I-B, W is CH and X is N.Or, each W and X is independently CH.

In another embodiment, the present invention provides compounds offormula II-A:

wherein ring Z, R², Q, and R^(Q) are as defined above.

In one embodiment, the present invention provides a method of inhibitingone or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 activity in:

-   -   (a) a patient; or    -   (b) a biological sample;

comprising administering to said patient, or contacting said biologicalsample with a compound of formula I:

or a pharmaceutically acceptable salt thereof;

wherein Z, R^(M), R^(N), W, X, Q, and R^(Q) are defined above.

In one embodiment, the present invention provides a method of inhibitingone or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 activity in:

-   -   (a) a patient; or    -   (b) a biological sample;

comprising administering to said patient, or contacting said biologicalsample with a compound of formula II:

or a pharmaceutically acceptable salt thereof;

wherein Z, R^(M), R^(N), Q, and e are defined above.

In another embodiment, the present invention provides compounds of Table1 below.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

USES, FORMULATION AND ADMINISTRATION

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels and/or calcium channels,and thus the present compounds are useful for the treatment of diseases,disorders, and conditions including but not limited to acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, and incontinence.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel orcalcium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments, a method for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain is provided comprising administering an effectiveamount of a compound or a pharmaceutically acceptable composition to asubject in need thereof. In certain other embodiments, a method for thetreatment or lessening the severity of radicular pain, sciatica, backpain, head pain, or neck pain is provided comprising administering aneffective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In still other embodiments, amethod for the treatment or lessening the severity of severe orintractable pain, acute pain, postsurgical pain, back pain, tinnitis orcancer pain is provided comprising administering an effective amount ofa compound or a pharmaceutically acceptable composition to a subject inneed thereof.

In certain embodiments of the present invention, an “effective amount”of the compound or pharmaceutically acceptable composition is thatamount effective for treating or lessening the severity of one or moreof acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex, and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels or calcium channels,preferably N-type calcium channels. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2, and thus, without wishing to be bound by any particular theory,the compounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV 1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2, is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to asa “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediatedcondition or disorder”. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity of oneor more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theexamples herein, or according to methods available to one of ordinaryskill in the art.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as ASS (Aspirin), Choline magnesium trisalicylate, Diflunisal;fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles suchas Phenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of sodium ion channels in biological and pathologicalphenomena; and the comparative evaluation of new sodium ion channelinhibitors.

EXAMPLES 5-Formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide

5-Formylamino-naphthalene-1-sulfonyl chloride (0.25 g, 0.93 mmol),2-aminothiazole (0.09 g, 0.93 mmol) and pyridine (1.00 ml) were stirredunder N₂ at 25° C. for 19 h. The solution was purified via silica gelchromatography using 3% MeOH/97% CH₂Cl₂ to obtain5-formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a whitesolid (150 mg, 49%). LC/MS (10-99% CH₃CN), M/Z: M+1 obs=334.20;t_(R)=1.93 min.

5-Amino-naphthalene-1-sulfonic acid thiazol-2-ylamide

A solution of 5-formylamino-naphthalene-1-sulfonic acidthiazol-2-ylamide (350.0 mg, 1.0 mmol), KOH (168.0 mg, 3.0 mmol), EtOH(1.0 ml) and H₂O (0.5 ml) was heated at 60° C. for 6 h. The mixtures wasthen cooled to 0° C., and neutralized with AcOH (3.0 mmol). The formedprecipitate was filtered and dried under vacuum to give5-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a light tansolid (280 mg, 92%). ¹H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.5 Hz, 1H),8.11 (dd, J=7.2, 1.0 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.45-7.42 (m, 1H),7.32-7.28 (m, 1H), 7.19 (d, J=4.6 Hz, 1H), 6.77-6.73 (m, 2H), 5.90 (s,2H). LC/MS (10-99% CH₃CN), M/Z: M+1 obs=306.10; t_(R)=1.12 min.

2-Indol-1-O—N-[5-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-propionamide

A solution of 5-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide(50.00 mg, 0.16 mmol), 2-Indol-1-yl-propionic acid (30.00 mg, 0.16mmol), BOP-reagent (71.00 mg, 0.16 mmol), triethylamine (23.00 μl, 0.16mmol) and DMF (0.30 ml) was stirred at 25° C. for 17 h. The reaction waspurified via preparative reverse phase HPLC to obtain2-(3-chloro-4-fluoro-phenoxy)-N-[5-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide.LC/MS (10-99% CH₃CN), M/Z: M+1 obs=477.10; t_(R)=3.05 min.

General Procedure 1:

Under N₂ at −78° C., the acid chloride (0.10 mmol) was added to amixture of 5-Amino-naphthalene-1-sulfonic acid thiazol-2-ylamide (30.0mg, 0.1 mmol), triethylamine (30.0 μl, 0.1 mmol) and CH₂Cl₂ (200.0 ml).After warming up to 25° C. and stirring overnight, the reaction mixturewas purified via preparative reverse phase HPLC (10-99% CH₃CN—H₂O) togive the desired product.

2-(3-Chloro-4-fluoro-phenoxy)-N-[5-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide

Synthesized according to general procedure 1. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=492.3; t_(R)=3.08 min.

3,4-Dichloro-N-[5-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-benzamide

Synthesized according to general procedure 1. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=478.0; t_(R)=3.20 min.

4-Acetamidonaphthalene-1-sulfonic acid

To a suspension of 4-amino-1-naphthalene sulfonic acid (10.0 g, 44.8mmol) in 10 ml MeOH was added 5 N NaOMe (9 ml). The mixture wassonicated to effect complete solution. The solvent was evaporated toprovide the sodium salt of -amino-1-naphthalene sulfonic acid as a whitesolid. This solid was suspended in 100 ml acetic anhydride and heated at110° C. for 2½ h. Adding some MeOH to the cooled mixture andco-evaporating with 3×100 ml toluene gave the Na-salt of4-acetamidonaphthalene-1-sulfonic acid as a white powder.

4-Acetamidonaphthalene-1-sulfonyl chloride

At 0° C., 4-acetamidonaphthalene-1-sulfonic acid (5 g, 19 mmol) wasslowly added to chlorosulfonic acid (25 ml). The mixture was allowed towarm to RT over 30 minutes and then stirred for 2 h. After slowly addingthe reaction mixture to ice water, a fine yellow precipitate formedwhich was filtered, washed with water and dried under vacuum to give4-acetamidonaphthalene-1-sulfonyl chloride (4.73 g, 87%). LC/MS (10-99%CH₃CN), M/Z: M+1 obs=284.0; t_(R)=3.06 min.

N-[4-(Thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide

To a solution of 4-acetamidonaphthalene-1-sulfonyl chloride (3.69 g,2.42 mmol) and pyridine (2 ml) was added 2-aminothiazole (0.24 g, 2.42mmol). This mixture was stirred at RT for 72 h. Purification via silicagel chromatography (first using 2% MeOH in CH₂Cl₂ to wash out remainingamine, then using 8% MeOH in CH₂Cl₂) gaveN-[4-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide (0.48 g, 57%).LC/MS (10-99% CH₃CN), M/Z: M+1 obs=348.10; t_(R)=1.78 min.

4-Amino-naphthalene-1-sulfonic acid thiazol-2-ylamide

N-[4-(Thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide (0.48 g, 1.38mmol) was dissolved in 0.5 M NaOMe (20 ml) and heated at 70° C. for 16h. After the solvents were evaporated, a 2:1 EtOH:H₂O mixture (6 ml) anda few drops of AcOH were added. While stirring the mixture, aprecipitate formed which was filtered and dried under vacuum to give4-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide (0.31 g, 73%).LC/MS (10-99% CH₃CN), M/Z: M+1 obs=306.0; t_(R)=2.04 min.

General Procedure 2:

To a solution of 4-Amino-naphthalene-1-sulfonic acid thiazol-2-ylamide(40 mg, 0.13 mmol) in CH₂Cl₂ (0.50 ml), was added triethylamine (20 μl,0.13 mmol) and cooled to −78° C. Then the acetyl chloride (0.13 mmol)was added and the mixture was allowed to warm to RT. Purification viapreparative reverse phase HPLC (10-99% CH₃CN—H₂O) gave the desiredproduct.

2-(4-Chloro-phenoxy)-N-[4-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide

Synthesized according to general procedure 2. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=474.0; t_(R)=3.12 min.

2-Phenoxy-N-[4-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide

Synthesized according to general procedure 2. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=440.2; t_(R)=2.93 min.

2,2,2-Trifluoro-N-(quinolin-8-yl)acetamide

To a stirring solution of aminoquinoline (1.0 g, 6.89 mmol),triethylamine (960.0 μl, 6.9 mmol) and CH₂Cl₂ (20.0 ml), at −78° C. wasadded dropwise trifluoroacetic anhydride (960.0 μl, 6.9 mmol). Thesolution was allowed to warm to 25° C. over a period of 30 minutesbefore it was purified via silica gel chromatography (1:1 Hexanes:EtOAc)to obtain the product as a white solid. LC/MS (10-99% CH₃CN), M/Z: M+1obs=241.2; t_(R)=3.38 min. ¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H),9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.50 (dd, J=8.3, 1.7 Hz, 1H), 8.36 (dd,J=7.6, 1.3 Hz, 1H), 7.92 (dd, J=8.3, 1.2 Hz, 1H), 7.72-7.68 (m, 2H).

8-(2,2,2-Trifluoroacetamido)quinoline-5-sulfonyl chloride

Under N₂ at 25° C., 2,2,2-trifluoro-N-(quinolin-8-yl)acetamide (5.0 g,20.8 mmol) was added to chlorosulfonic acid (15 ml) and then heated at80° C. for 19 h. The mixture was then poured into ice-water (200 ml),followed by addition of EtOAc (300 ml). The organic layer was passedthrough a short bed of silica gel followed by EtOAc (700 ml) and thenevaporated and triturated with Et₂O to give the product as a light tansolid (2.2 g, 31%). ¹H NMR (400 MHz, CDCl₃) δ 11.02 (s, 1H), 9.19 (dd,J=8.8, 1.4 Hz, 1H), 9.05 (dd, J=4.2, 1.4 Hz, 1H), 8.84 (d, J=8.5 Hz,1H), 8.48 (d, J=8.5 Hz, 1H), 7.85 (dd, J=8.8, 4.2 Hz, 1H).

2,2,2-Trifluoro-N-[5-(thiazol-2-ylsulfamoyl)-quinolin-8-yl]-acetamide

Under N₂ at 25° C., 8-(2,2,2-trifluoroacetamido)quinoline-5-sulfonylchloride (500.0 mg, 1.5 mmol), 2-aminothiazole (148.0 mg, 1.5 mmol) andpyridine (500 ml) were stirred for 17 h. The solution was then purifiedvia silica gel chromatography (5% MeOH, 95% CH₂Cl₂) to obtain a mixturewhich was 85% pure by HPLC (254 nm). The solid was triturated with 9:1hexanes:Et₂O to give the product as a white solid (200 mg, 33%). LC/MS(10-99% CH₃CN), M/Z: M+1 obs=403.2; t_(R)=3.06 min. ¹H NMR (400 MHz,DMSO-d6) δ 12.91 (s, 1H), 11.14 (s, 1H), 9.14-9.09 (m, 2H), 8.50 (d,J=8.1 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.92-7.89 (m, 1H), 7.25 (d, J=4.6Hz, 1H), 6.86 (d, J=4.5 Hz, 1H).

8-Amino-quinoline-5-sulfonic acid thiazol-2-ylamide

A mixture of2,2,2-trifluoro-N-[5-(thiazol-2-ylsulfamoyl)-quinolin-8-yl]-acetamide(0.20 g, 0.49 mmol), KOH (85.0 mg, 1.5 mmol), EtOH (500 ml) and H₂O (250ml) was stirred at 25° C. for 1 h. The mixture formed a solution after15 minutes, followed by the formation of a precipitate. First H₂O (1ml), then AcOH (85 μl, 1.5 mmol) was added. The formed solid wasfiltered and dried under vacuum to give the product as a white solid(120 mg, 80%). LC/MS (10-99% CH₃CN), M/Z: M+1 obs=307.3; t_(R)=1.73 min.¹H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J=8.7, 1.6 Hz, 1H), 8.78 (dd,J=4.1, 1.6 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.65-7.62 (m, 1H), 7.16 (d,J=4.6 Hz, 1H), 6.81-6.73 (m, 4H).

General Procedure 3:

A mixture of 8-amino-quinoline-5-sulfonic acid thiazol-2-ylamide (30.0mg, 0.1 mmol), triethylamine (15.0 μl, 0.10 mmol) and CH₂Cl₂ (200 μl)was cooled to −78° C., then the acid chloride (0.1 mmol) was added.After warming to RT for ca. 1 h, preparative reverse phase HPLC (10-99%CH₃CN—H₂O) was used to obtain the desired product.

2-Fluoro-N-[5-(thiazol-2-ylsulfamoyl)-quinolin-8-yl]-benzamide

Synthesized according to general procedure 3. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=429.3; t_(R)=2.98 min.

2-(3-Chloro-4-fluoro-phenoxy)-N-[5-(thiazol-2-ylsulfamoyl)-quinolin-8-yl]-acetamide

Synthesized according to general procedure 3. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=493.1; t_(R)=3.13 min. ¹H NMR (400 MHz, DMSO-d6) δ 12.83 (s,1H), 10.87 (s, 1H), 9.10-9.05 (m, 2H), 8.70 (d, J=8.3 Hz, 1H), 8.26 (d,J=8.3 Hz, 1H), 7.87-7.84 (m, 1H), 7.44-7.39 (m, 2H), 7.23 (d, J=4.6 Hz,1H), 7.17-7.13 (m, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.00 (s, 2H).

2-Phenoxy-N-[5-(thiazol-2-ylsulfamoyl)-quinolin-8-yl]-propionamide

Synthesized according to general procedure 3. LC/MS (10-99% CH₃CN), M/Z:M+1 obs=455.3; t_(R)=3.02 min.

Analytical data for compounds of the present invention is illustratedbelow in Table 2.

TABLE 2 LC/MS LC/RT Cmpd # M + 1 min 1 429.3 2.98 2 440.2 2.93 3 474.33.06 4 447.3 3.05 5 493.1 3.13 6 455.3 3.02 7 474.3 3.06 8 454.2 2.77 9492.2 3.16 10 403.2 3.06 11 473.8 3.13 12 477.1 3.05 13 492.3 3.08 14474 3.12 15 441.3 2.98 16 478 3.2 17 479.3 3.28 18 496.4 3.49

Assays for Detecting and Measuring NAV Inhibition Properties of Compound

Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

1) On the day of the assay, medium is aspirated and cells are washedtwice with 225 μL of Bath Solution #2 (BS#2).

2) A 15 μM CC2-DMPE solution is prepared by mixing 5 mM coumarin stocksolution with 10% Pluronic 127 1:1 and then dissolving the mix in theappropriate volume of BS#2.

3) After bath solution is removed from the 96-well plates, the cells areloaded with 80 μL of the CC2-DMPE solution. Plates are incubated in thedark for 30 minutes at room temperature.

4) While the cells are being stained with coumarin, a 15 μL oxonolsolution in BS#2 is prepared. In addition to DiSBAC₂(3), this solutionshould contain 0.75 mM ABSC1 and 30 μL veratridine (prepared from 10 mMEtOH stock, Sigma #V-5754).

5) After 30 minutes, CC2-DMPE is removed and the cells are washed twicewith 225 μL of BS#2. As before, the residual volume should be 40 μL.

6) Upon removing the bath, the cells are loaded with 80 μL of theDiSBAC₂(3) solution, after which test compound, dissolved in DMSO, isadded to achieve the desired test concentration to each well from thedrug addition plate and mixed thoroughly. The volume in the well shouldbe roughly 121 μL. The cells are then incubated for 20-30 minutes.7) Once the incubation is complete, the cells are ready to be assayed onVIPR® with a sodium addback protocol. 120 μL of Bath solution #1 isadded to stimulate the NaV dependent depolarization. 200 μL tetracainewas used as an antagonist positive control for block of the NaV channel.Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\;{nm}} - {background}_{460\;{nm}}} \right)}{\left( {{intensity}_{580\;{nm}} - {background}_{580\;{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R═R_(f)/R_(i) is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compoundSolutions [mM]

-   Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH    7.4 with NaOH-   Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4    with KOH (final K concentration ˜5 mM)-   CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at    −20° C.-   DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.-   ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at    room temperature    Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV 1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

-   -   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO    -   10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO    -   10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO    -   200 mM ABSC1 in H₂O    -   Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented        with 10 mM HEPES (Gibco #15630-080)        Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is added to wells containing washed cells, resultingin a 10 μM final staining concentration. The cells are stained for 30minutes in the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1:

The required amount of 10 mM DISBAC₂(3) is added to a 50 ml conical tubeand mixed with 1 μL 10% pluronic for each mL of solution to be made andvortexed together. Then HBSS/HEPES is added to make up 2× solution.Finally, the ABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the2×DiSBAC₂(3) w/ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

-   -   Assay buffer #1    -   140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10        mM glucose, pH 7.40, 330 mOsm    -   Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO    -   Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO    -   Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO    -   ABSC1 stock (400×): 200 mM ABSC1 in water        Assay Protocol    -   1. Insert or use electrodes into each well to be assayed.    -   2. Use the current-controlled amplifier to deliver stimulation        wave pulses for 3 s. Two seconds of pre-stimulus recording are        performed to obtain the un-stimulated intensities. Five seconds        of post-stimulation recording are performed to examine the        relaxation to the resting state.        Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\;{nm}} - {background}_{460\;{nm}}} \right)}{\left( {{intensity}_{580\;{nm}} - {background}_{580\;{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R═R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 m in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl₂ (0.4), NiCl₂ (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a MultiClamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 HEPES, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 HEPES). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

Activity data for selected compounds is illustrated below in Table 3.

TABLE 3 Cmpd. No. IC₅₀ 1 + 2 ++ 3 +++ 4 + 5 + 6 ++ 7 +++ 8 ++ 9 ++ 10 +11 ++ 12 +++ 13 +++ 14 ++ 15 + 16 +++ 18 ++ “+++” means an activity ofless than 5 μM. “++” means an activity between 5 μM and 20 μM. “+” meansan activity of greater than 20 μM.

“+++” means an activity of less than 5 μM. “++” means an activitybetween 5 μM and 20 μM. “+” means an activity greater than 20 μM.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein: one of X and W is N and the other of X and W is CH; ring Z is a 5-7 membered unsaturated or aromatic ring having at least one ring heteroatom selected from O, S, N, or NH, wherein Z is optionally substituted with up to z occurrence of R^(Z); z is 0 to 4; each R^(z) is independently selected from R¹, R², R³, R⁴, or R⁵; the SO₂ group is attached to either carbon no, 1 or 2; the ring containing W and X is optionally substituted with up to 4 substituents selected from halo, CN, NO₂, CF₃, OCF₃, OR⁶, SR6, S(O)R², SO₂R², NH₂, N(R²)₂, COOR², or C1-C6 straight or branched alkylidine chain, wherein up to two non-adjacent methylene units of said alkylidine are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, or —NR²SO₂NR²—; Q is a bond or is a C1-C6 straight or branched alkylidine chain, wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or a spirocycloalkylene moeity; R^(Q) is a C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, S, N, or NH, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from O, S, N, or NH; wherein R^(Q) is optionally substituted with up to 4 substituents selected from R¹, R², R³, R⁴, or R⁵; R^(M) and R^(N) are independently R²; R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶, or (CH₂)_(n)—Y; or two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; n is 0, 1, or 2; Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶, or OR⁶; R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionally substituted with up to 2 substituents independently selected from R¹, R⁴, or R⁵; R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 substituents, independently selected from R¹, R², R⁴, or R⁵; R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂, OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵), SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶, SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂, C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶), NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵); R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 R¹ substituents; R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with a R⁷ substituent; R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R⁷ is optionally substituted with up to 2 substituents independently chosen from H, C1-C6 aliphatic, or (CH₂)_(m)—Z′ wherein in is 0-2; Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH, C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and R⁸ is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl.
 2. The compound according to claim 1, Z is an optionally substituted ring selected from:


3. The compound according to claim 2, wherein Z is selected from:


4. The compound according to claim 1, wherein z is 0-2.
 5. The compound according to claim 1, wherein each R^(Z) is independently selected from R¹, R², or R⁵.
 6. The compound according to claim 1, wherein each R^(Z) is independently selected from a hydrogen, halo, OR⁶, a C1-C6 aliphatic, or an optionally substituted group independently selected from C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring; wherein said cycloaliphatic, said aryl, said heterocyclic, or said heteroaryl is optionally substituted with up to 3 substituents independently selected from R¹, R², R⁴, or R⁵.
 7. The compound according to claim 6, wherein each R^(Z) is independently selected from hydrogen, halo, O(C1-C6 alkyl), C1-C6 alkyl, C3-C8 cycloalkyl, or phenyl.
 8. The compound according to claim 1, wherein X is N and W is CH.
 9. The compound according to claim 1, wherein X is CH and W is N.
 10. The compound according to claim 1, wherein R^(M) is hydrogen.
 11. The compound according to claim 1, wherein R^(N) is hydrogen.
 12. The compound according to claim 1, wherein Q is selected from a bond, or a C1-C6 straight or branched alkylidene chain, wherein up to two methylene units of said alkylidene is independently replaced by O, S, OCO, NH, N(C1-C4 alkyl), or a spirocycloalkylene group.
 13. The compound according to claim 12, wherein Q is —-X₂—(X₁)_(p)—, wherein: X₂ is a bond or C1-C6 aliphatic, optionally substituted with up to two substituents independently selected from R¹, R⁴, or R⁵; p is 0 or 1; and X₁ is O, S, or NR².
 14. The compound according to claim 13, wherein X₂ is a bond, C1-C6 alkyl, or C2-C6 alkylidene, and said alkyl and alkylidene are independently and optionally substituted with R¹ or R⁴.
 15. The compound according to claim 14, wherein X₂ is selected from a bond, —CH₂—, —CH₂—CH₂—, —(CH₂)₃—, —C(Me)₂-, —CH(Me)—, —C(Me)═CH—, —CH═CH—, —CH(Ph)—, —CH₂—CH(Me)—, —CH(Et)—, or —CH(i-Pr)—.
 16. The compound according to claim 1, wherein R^(Q) is an optionally substituted C₁₋₆ aliphatic.
 17. The compound according to claim 16, wherein R^(Q) is optionally substituted with up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), (C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.
 18. The compound according to claim 1, wherein R^(Q) is an optionally substituted phenyl or naphthyl.
 19. The compound according to claim 18, wherein R^(Q) is optionally substituted with up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.
 20. The compound according to claim 19, wherein R^(Q) is selected from:


21. The compound according to claim 1, wherein R^(Q) is an optionally substituted 3-8 membered cycloaliphatic ring.
 22. The compound according to claim 21, wherein R^(Q) is an optionally substituted ring selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
 23. The compound according to claim 1, wherein R^(Q) is an optionally substituted 5-6 membered monocyclic, unsaturated, partially substituted, or aromatic ring containing up to 3 heteroatoms independently selected from O, S, N, or NH.
 24. The compound according to claim 23, wherein R^(Q) is an optionally substituted ring selected from:


25. The compound according to claim 24, wherein R^(Q) is optionally fused to an optionally substituted phenyl ring.
 26. The compound according to claim 1, wherein R^(Q) is an optionally substituted 8-10-membered bicyclic, heterocyclic or heteroaromatic, ring.
 27. The compound according to claim 26, wherein R^(Q) is an optionally substituted ring selected from:


28. The compound according to claim 1, wherein R^(Q) is selected from 2-fluoro-phen-1-yl, phenyl, 3-chloro-phen-1-yl, 4-chloro-phen-1-yl, 4-tert-butyl-phen-1-yl, 2,5-difluoro-phen-1-yl, 3,4-dichloro-phen-1-yl, 3-chloro-4-fluoro-phen-1-yl, or indol-1-yl.
 29. The compound according to claim 1, wherein said compound is selected from formula I-A, or formula I-B:


30. The compound according to 29, wherein X is N and W is CH.
 31. The compound according to 29, wherein X is CH and W is N.
 32. A compound selected from


33. A pharmaceutical composition comprising a compound according to claim 1 or 32, and a pharmaceutically acceptable carrier, adjuvant, or a vehicle. 